Boehringer abandons PDE-targeted Alzheimer’s drug

Boehringer Ingelheim has said it will halt development of its Alzheimer’s disease drug BI 409306 after it failed to hit the mark in mid-stage trials but will keep testing it in schizophrenia.

The demise of the drug is doubly disappointing as BI 409306 had a different mechanism of action to many of the ever-growing list of Alzheimer’s candidates that have had to be abandoned after failing clinical trials.

The drug was an inhibitor of phosphodiesterase (PDE) 9A, a drug target for cognitive decline because the enzyme reduces brain levels of the second messenger cyclic guanosine monophosphate (cGMP), which transduces signals by the neurotransmitters nitric oxide and glutamate. This pathway modulates synaptic transmission and plasticity in the hippocampus and cerebral cortex and is typically depressed in the brains of Alzheimer’s patients.

“This is what research is about: disappointments are a daily experience in science, but even these clinical trial results will add to the understanding of brain function and contribute to future progress in this area,” said Jan Poth, head of CNS and Immunology research at Boehringer.

BI 409306 was tested in two phase II trials involving around 450 patients with established cognitive impairment due to Alzheimer’s but was unable to show any improvement over placebo in slowing down the rate of cognitive decline.

The company says it will now shift the focus of BI 409306 to schizophrenia, another disease which seems to involve disruption of the glutamate pathway. It has two studies ongoing that are hoping to show that the drug can prevent relapse as well as first psychotic episodes in schizophrenia patients.

It’s not the end of Boehringer’s attempts to find new therapies for Alzheimer’s however. It is currently planning phase II trials of BI 425809, a glycine transport (glyt1) inhibitor that also affects the glutamate pathways in the central nervous system, in a range of CNS disorders including dementia.

Efforts to develop new therapies for Alzheimer’s have resulted in a litany of failures, many involving drugs targeting the beta amyloid pathway that leads to the formation of the characteristic plaques that appear in the brains of people with the disease. Various other treatment approaches have also been tried and failed, including drugs targeting the serotonin pathway as well as diabetes medicine pioglitazone.

An anti-amyloid drug developed by Boehringer and Eisai missed an interim analysis last December and now looks unlikely to show efficacy although final results are not expected until later this year.

Currently-registered drugs such as cholinesterase inhibitors, which boost neurotransmitter levels in the brain, are palliative at best.